title: Nitroxyl (HNO): A novel approach for the acute treatment of heart failure.
abstract: BACKGROUND
  The nitroxyl (HNO) donor, Angeli's salt, exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cAMP independent. Its clinical usefulness is limited by chemical instability and cogeneration of nitrite which itself has vascular effects. Here, we report on effects of a novel, stable, pure HNO donor (CXL-1020) in isolated myoctyes and intact hearts in experimental models and in patients with heart failure (HF).
  
  
  RESULTS
  CXL-1020 converts solely to HNO and inactive CXL-1051 with a t1/2 of 2 minutes. In adult mouse ventricular myocytes, it dose dependently increased sarcomere shortening by 75% to 210% (50-500 μmol/L), with a ≈30% rise in the peak Ca(2+) transient only at higher doses. Neither inhibition of protein kinase A nor soluble guanylate cyclase altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced left ventricular end-diastolic pressure and myocardial oxygen consumption while increasing ejection fraction from 27% to 40% and maximal ventricular power index by 42% (both P<0.05). In conscious dogs with tachypacing-induced HF, CXL-1020 increased contractility assessed by end-systolic elastance and provided venoarterial dilation. Heart rate was minimally altered. In patients with systolic HF, CXL-1020 reduced both left and right heart filling pressures and systemic vascular resistance, while increasing cardiac and stroke volume index. Heart rate was unchanged, and arterial pressure declined modestly.
  
  
  CONCLUSIONS
  These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function and present first-in-man evidence for its potential usefulness in HF.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01096043, NCT01092325.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, MI.
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Carlo Gabriele
authors.initials: CG
authors.lastname: Tocchetti
authors.forename: Mengjun
authors.initials: M
authors.lastname: Wang
authors.forename: Samantapudi
authors.initials: S
authors.lastname: Daya
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
authors.forename: Richard S
authors.initials: RS
authors.lastname: Tunin
authors.forename: Reza
authors.initials: R
authors.lastname: Mazhari
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Douglas
authors.initials: D
authors.lastname: Cowart
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005609:Free Radicals; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D009589:Nitrogen Oxides / Q000008:administration & dosage*; D013318:Stroke Volume / Q000187:drug effects*; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D000975:Antioxidants; D005609:Free Radicals; D009589:Nitrogen Oxides; C039900:nitroxyl
keywords: cardiomyopathies; heart contractility; humans; muscle cells; nitroxyl; pharmacology; vasodilator drugs